Hepatitis C virus (HCV) is the causative agent of non-A, non-B chronic liver disease in the human population. It has been well documented that the majority of HCV infections lead to the establishment of persistent chronic hepatitis with possible progression to liver cirrhosis and/or hepatocellular carcinoma. Analysis of HCV infected patients and chimpanzees, the only non-human species that supports viral replication, has indicated both humoral and cellular immune response to viral infection. The CD8+ cytotoxic T cell (CTL) response to HCV is both polyclonal and multispecific, however, in most cases, it is insufficient in clearing the virus from the infected host. Although understanding the basis by which HCV can persist in the face of a peripheral and intrahepatic CTL response is of worldwide importance, the mechanisms of HCV-mediated immune evasion remain largely unknown due to a lack of small animal models and tissue culture infections systems. Consequently, the focus of this proposal will be to analyze the global mechanisms of HCV viral persistence in the host. This will entail the production of a tissue culture model to examine the effects of HCV gene expression on the mechanisms by which HCV escapes the CD8+ cytotoxic T cell response. This work will also produce animal models of HCV replication to examine the antiviral effects of cytokines on HCV RNA in vivo.